<i>De novo</i> genesis of retinal ganglion cells by targeted expression of <i>Klf4 in vivo</i>

Abstract

Retinal ganglion cell (RGC) degeneration is a hallmark of glaucoma, the most prevalent cause of irreversible blindness. Thus, therapeutic strategies are needed to protect and replace these projection neurons. One innovative approach is to promote <i>de novo</i> genesis of RGCs via manipulation of endogenous cell sources. Here, we demonstrate that the pluripotency regulator gene Krüppel-like factor 4 (<i>Klf4</i>) is sufficient to change the potency of lineage-restricted retinal progenitor cells to generate RGCs <i>in vivo</i> Transcriptome analysis disclosed that the overexpression of <i>Klf4</i> induces crucial regulators of RGC competence and specification, including <i>Atoh7</i> and <i>Eya2</i> In contrast, loss-of-function studies in mice and zebrafish demonstrated that <i>Klf4</i> is not essential for generation or differentiation of RGCs during retinogenesis. Nevertheless, induced RGCs (iRGCs) generated upon <i>Klf4</i> overexpression migrate to the proper layer and project axons aligned with endogenous fascicles that reach the optic nerve head. Notably, iRGCs survive for up to 30 days after <i>in vivo</i> generation. We identified <i>Klf4</i> as a promising candidate for reprogramming retinal cells and regenerating RGCs in the retina.This article has an associated 'The people behind the papers' interview.